Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO2F2)

A SO2F2-mediated ring-opening cross-coupling of cyclobutanone oxime derivatives with alkenes was developed for the construction of a range of δ-olefin-containing aliphatic nitriles with (E)-configuration selectivity. This new method features wide substrate scope, mild conditions, and direct N–O activation.


Introduction
As an important functional group in organic molecules, the nitrile group is commonly present in functional materials [1,2], nanoscale drug carriers [3][4][5], biologically valuable molecules and drugs (Scheme 1) [6,7]. There are over 70 nitrile-containing drugs approved by the FDA for various indications and more than 140 additional nitrile-containing leads in clinical investigation [8]. Looking into changing the physicochemical properties, in the field of drug discovery, it is important to explore solutions to introduce nitrile groups into a molecule for enhancing the interaction between the drug candidate and the target protein, to further improve the efficacy of the potential drug [9]. The nitrile group can also function as a metabolic blocking site to inhibit the oxidative metabolism of molecules to improve metabolic stability in vivo [10]. Consequently, the development of novel synthetic methods and strategies toward nitrile group construction continues to be a focus for synthetic chemists.
The cross-coupling reactions of C-C bonds catalyzed by transition-metal complexes play a crucial role in modern organic synthesis, as they make it feasible to synthesize complex structures from available components [11][12][13]. Indeed, the formation of C(sp 2 )-C(sp 3 ) bonds by cross-coupling has developed rapidly in recent years [14][15][16], but it still remains less advanced than the synthesis of C(sp 2 )-C(sp 2 ) bonds [17,18]. This is attributed to the electron-richness of the C(sp 3 ) carbon, which leads to side reactions of the alkyl intermediates [14,19,20]. Besides, most of the C(sp 2 )-C(sp 3 ) reactions employ organic halides or Scheme 1: Representative nitrile-containing functional materials, drug carriers, and medicines. organometallic reagents [21][22][23], which are not environmentally friendly.
On the other hand, sulfuryl fluoride (SO 2 F 2 ) [43], a kind of inexpensive (about 1 $/kg), abundant, and relatively inert electrophile and one of the major sulfur fluoride exchange (SuFEx) click chemistry reagents [44,45], has been successfully applied as an electrophile to react with hydroxy groups to generate fluorosulfonate esters, being activated intermediates for a variety of transformations [46][47][48][49][50][51][52][53][54][55][56][57][58]. Lately, we discovered the SO 2 F 2 -mediated transformation of primary alcohols to nitriles, involving an aldoxime sulfonyl ester intermediate (Scheme 2c) [59]. Drawing inspiration from these excellent works, we contemplated that the N-O bond of cyclobutanone oxime derivatives could be activated by SO 2 F 2 in situ to enable cleavage of the C-C bond, which could achieve this transformation without going through inefficient pre-introduction of electrophores. Herein, we describe how this concept has been translated into experimental reality, developing a new SO 2 F 2 -mediated C-C single bond cleavage method for constructing δ-olefin-containing aliphatic nitriles.

Results and Discussion
We started our investigation by selecting cyclobutanone oxime (1a) and 1,1-diphenylethylene (2a) as model starting materials to testify the feasibility of this proposed transformation in the presence of N,N-diisopropylethylamine (DIPEA) and Cu(OTf) 2 in dioxane/PhCF 3 (1:1) under an SO 2 F 2 atmosphere at 100 °C. The desired product 6,6-diphenylhex-5-enenitrile (3aa) was obtained in 24% yield (Table 1, entry 1) and according to the control experiment, SO 2 F 2 is essential for the reaction to proceed (Table 1, entry 2). Encouraged by the preliminary result, we then screened a large variety of conditions as shown in Table 1 in order to improve the efficiency of the transformation. The investigation of the solvent effect revealed that in 1,4dioxane the transformations performed the best (  entries 13 and 14), which could probably be attributed to the decomposition of the highly active sulfonyl ester intermediate. The reaction time was also screened and the yield did not change within the accuracy errors when the time was extended (Table 1, entry 15) and among the screened reaction times, 12 hours were chosen as the optimal conditions (see Supporting Information File 1 for more details).
With the optimized reaction conditions in hand, a range of other substrates possessing representative functional groups was em-ployed subsequently to evaluate the reaction scope and limitations (Scheme 3). Under the optimized conditions, alkenes 2b-e with varying steric effects underwent smooth reaction, yielding the corresponding products 3ab-ae in moderate to good yields (56-68%). Notably, the efficiency of this transformation was greatly impacted by the electronic effect on the aromatic rings of the olefins. Alkenes with electron-donating groups on their aromatic rings showed higher yields of the corresponding products as compared to those with electron-withdrawing groups (3af-ar). Furthermore, the desired products were not even obtained when the starting materials were connected to extra strong electron-withdrawing groups (such as a nitro group) on their aromatic rings. In addition, a series of cyclobutanone oxime derivatives were also smoothly transformed into the corresponding nitriles 3ba-da in excellent yields.
Interestingly, when the loading of CH 3 COOK was reduced to 2 equivalents, we obtained a mixture of unsaturated nitrile 3aa and saturated nitrile 4 after column chromatography  (Scheme 4). We speculated that the reduction of the base equivalent may induce the ionization of 1a and facilitate the ultimate addition process. The selectivity of bases for different processes may attract significant attention for further applications.
In order to understand the mechanism of the aforementioned transformation, some experimental investigations were performed as described in Scheme 5. Under the promotion of the base, cyclobutanone oxime preliminarily reacts with SO 2 F 2 , generating the activated precursor fluorosulfonate, which further reacts with the alkene 2a in the presence of the copper catalyst under Ar atmosphere for 9 h (Scheme 5a). The corresponding product was successfully obtained in 45% yield, which indirectly proved the existence of an oxime sulfonyl ester intermediate (fluorosulfonate). As shown in Scheme 5b, in the presence of one equivalent of TEMPO, a commonly used radical scavenger, the yield of 3aa significantly decreased, in addition, the reaction was completely inhibited when the amount of added TEMPO was increased to 2 equivalents.
Based upon the preliminary results and previous reports of this class of transformation [26,30,36,37,42,60,61], a plausible mechanism for the base-promoted, SO 2 F 2 -mediated ringopening cross-coupling of cyclobutanone oxime derivatives with alkenes was proposed (Scheme 6

Conclusion
In conclusion, we have developed an SO 2 F 2 -mediated ringopening cross-coupling reaction of cyclobutanone oxime derivatives with alkenes for the synthesis of a class of novel elongated nitriles. The newly constructed δ-olefin-containing aliphatic nitriles possess E-configuration at the double bond. This transformation could be easily activated by SO 2 F 2 in situ without the need of pre-introduction of electrophores.

Supporting Information
Supporting Information File 1 Experimental information.

Funding
We are grateful to the National Natural Science Foundation of China (Grant No. 22071190) and Wuhan University of Technology for the financial support.